The objectives of this research are to elucidate basic principles and relationships associated with age-related changes in drug conjugation and the manner in which such changes alter drug action. Of primary interest is an examination of whether the increases after birth in conjugation of the drugs acetaminophen and salicylamide with glucuronic acid and the commensurate age-related reduction of sulfate conjugation alters the adverse effects of high doses of these drugs. Animals of various ages, including newborns, will be given the drugs and measurements of adverse effects made (e.g., histopathology, serum enzymes, LD50 etc.). In other experiments, the disposition of 14C-acetaminophen and 14C-salicylamide will be investigated in animals of various ages. The unchanged drugs and all of their metabolites will be determined in blood, tissues and urine. Correlations will be made between age, pattern of drug disposition and adverse drug effects. Experimentally-induced alterations in the rate of conjugation will be examined using isolated hepatocytes. These experiments are directed toward understanding how changes in rates of conjugation of acetaminophen with sulfate or glucuronic acid can alter drug conjugation by other pathways and the production of drug-induced cellular damage. In another group of experiments the fate of acetaminophen sulfate and acetaminophen glucuronide in animals poisoned with acetaminophen and in control animals will be studied. The purpose of these studies is to determine whether drug-induced hepatic necrosis can disrupt the compartmentalization of the liver cell thereby causing release of enzymes capable of hydrolyzing drug conjugates. The action would inrease concentrations of acetaminophen in the liver and increase its cytotoxic effects in that organ.